7fbl

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Thrombocorticin in complex with Ca2+ and mannose

Structural highlights

7fbl is a 2 chain structure with sequence from Corticium sp. (in: Fungi). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.419Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

THRCO_CORXX Binds to fucose and mannose in a calcium-dependent manner (in vitro) (Ref.2). Acts as an agonist for human thrombopoietin receptor MPL (in vitro) (PubMed:30978513, Ref.2). Binding of sugar-moieties may promote the interaction with human MPL on the cell surface (in vitro) (Ref.2). Catalyzes MPL dimerization and activation, and modulates internalization of the receptor (in vitro) (Ref.2). Exhibits proliferation activity in murine recombinant Ba/F3 cells expressing human MPL (Ba/F3-huMPL) (in vitro) (PubMed:30978513). Induces phosphorylation of STAT5 in recombinant Ba/F3-huMPL cells, possibly by stimulating MPL on the cell surface to transduce signals via Jak/STAT signaling pathway (in vitro) (PubMed:30978513, Ref.2). Does not aggregate rabbit erythrocytes, indicating absent lectin-like agglutination activity (in vitro) (PubMed:30978513).^[1] ^[2]

Publication Abstract from PubMed

N-glycan-mediated activation of the thrombopoietin receptor (MPL) under pathological conditions has been implicated in myeloproliferative neoplasms induced by mutant calreticulin, which forms an endogenous receptor-agonist complex that traffics to the cell surface and constitutively activates the receptor. However, the molecular basis for this mechanism is elusive because oncogenic activation occurs only in the cell-intrinsic complex and is thus cannot be replicated with external agonists. Here, we describe the structure and function of a marine sponge-derived MPL agonist, thrombocorticin (ThC), a homodimerized lectin with calcium-dependent fucose-binding properties. In-depth characterization of lectin-induced activation showed that, similar to oncogenic activation, sugar chain-mediated activation persists due to limited receptor internalization. The strong synergy between ThC and thrombopoietin suggests that ThC catalyzes the formation of receptor dimers on the cell surface. Overall, the existence of sugar-mediated MPL activation, in which the mode of activation is different from the original ligand, suggests that receptor activation is unpredictably diverse in living organisms.

A marine sponge-derived lectin reveals hidden pathway for thrombopoietin receptor activation.,Watari H, Kageyama H, Masubuchi N, Nakajima H, Onodera K, Focia PJ, Oshiro T, Matsui T, Kodera Y, Ogawa T, Yokoyama T, Hirayama M, Hori K, Freymann DM, Imai M, Komatsu N, Araki M, Tanaka Y, Sakai R Nat Commun. 2022 Nov 25;13(1):7262. doi: 10.1038/s41467-022-34921-2. PMID:36433967^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Watari H, Nakajima H, Atsuumi W, Nakamura T, Nanya T, Ise Y, Sakai R. A novel sponge-derived protein thrombocorticin is a new agonist for thrombopoietin receptor. Comp Biochem Physiol C Toxicol Pharmacol. 2019 Jul;221:82-88. PMID:30978513 doi:10.1016/j.cbpc.2019.04.003
↑ Watari H, Nakajima H, Atsuumi W, Nakamura T, Nanya T, Ise Y, Sakai R. A novel sponge-derived protein thrombocorticin is a new agonist for thrombopoietin receptor. Comp Biochem Physiol C Toxicol Pharmacol. 2019 Jul;221:82-88. PMID:30978513 doi:10.1016/j.cbpc.2019.04.003
↑ Watari H, Kageyama H, Masubuchi N, Nakajima H, Onodera K, Focia PJ, Oshiro T, Matsui T, Kodera Y, Ogawa T, Yokoyama T, Hirayama M, Hori K, Freymann DM, Imai M, Komatsu N, Araki M, Tanaka Y, Sakai R. A marine sponge-derived lectin reveals hidden pathway for thrombopoietin receptor activation. Nat Commun. 2022 Nov 25;13(1):7262. PMID:36433967 doi:10.1038/s41467-022-34921-2